A Multiple Dose Study of Grazoprevir (MK-5172) in Hepatitis C-Infected Participants (MK-5172-010)

A Multiple Dose Study to Evaluate Pharmacokinetics and Hepatitis C Virus RNA Dynamics Following Administration of MK-5172 in Hepatitis C Infected Patients

The goal of this study was to compare hepatic pharmacokinetics (PK) derived from liver tissue to plasma PK after administration of grazoprevir (MK-5172) to participants with chronic hepatitis C virus (HCV) infection. Participants will be randomized to one of four different liver ultrasound-guided Fine Needle Aspirate (FNA) schedules (at 4-, 8-, 24-, or 72-hours after the Day 7 dose).

Study Overview

• Status: Completed
• Conditions: Hepatitis C
• Intervention / Treatment: Drug: Grazoprevir

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• has a Body Mass Index (BMI) ≥18.5 kg/m² and ≤36.0 kg/m²
• has chronic compensated, genotype 1 HCV infection
• has no cirrhosis of the liver as confirmed by FibroSure®/Fibro Test® and/or local country procedure (e.g. transient elastography/Fibroscan)
• does not require anticoagulants, nonsteroidal anti-inflammatory agents, and aspirin for at least fourteen (14) days preceding the initial liver biopsy and continuing throughout the entire study
• if is a female participant of reproductive potential, is willing to use 2 medically acceptable forms of contraception for 2 weeks prior to start of treatment through 2 weeks after last study treatment
• if is a male participant with a partner(s) of reproductive potential, is willing to use 2 medically acceptable forms of contraception from first dose to 90 days after last dose

Exclusion criteria:

• has a history of stroke, chronic seizures, or major neurological disorder
• has received previous treatment with a direct-acting antiviral (DAA)
• has evidence of high grade bridging fibrosis from prior liver biopsy within 3 years of study entry
• has evidence or history of chronic hepatitis not caused by HCV infection including but not limited to non-HCV viral hepatitis, nonalcoholic steatohepatitis (NASH), drug-induced hepatitis, or autoimmune hepatitis
• has clinical or laboratory evidence of cirrhosis or other advanced liver disease
• has decompensated liver disease as indicated by a history of ascites, hepatic encephalopathy, or bleeding esophageal varices
• has been diagnosed with, or suspected of having, hepatocellular carcinoma (HCC)
• has clinically significant abnormality on an electrocardiogram (ECG)
• is co-infected with human immunodeficiency virus (HIV)
• is positive for Hepatitis B surface antigen (HBsAg) or other evidence of active Hepatitis B infection
• has a history of gastric bypass surgery, bowel resection or other disorder that may interfere with absorption
• has a history of clinically significant uncontrolled endocrine, gastrointestinal, cardiovascular, hematological, immunological, renal, respiratory, or genitourinary abnormalities or diseases
• has clinically significant neoplastic disease
• uses alcohol to excess, defined as greater than 3 glasses of alcoholic beverages (1 glass is approximately equivalent to: beer [354 mL], wine [118 mL], or distilled spirits [29.5 mL]) per day
• is a current regular user (including use of any illicit drugs) or history of drug (including alcohol) abuse within the last 3 months
• has undergone surgery, donation of 1 unit of blood (approximately 500 mL) or participation in another investigational study within a period of 4 weeks prior to the screening visit
• has a history of multiple and/or severe allergies, or anaphylactic reaction or intolerability to prescription or nonprescription drugs or food
• is pregnant or lactating
• is expecting to donate eggs or sperm

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Grazoprevir 100 mg; Participants received GZR 100 mg once daily (q.d.) for 7 days. Liver FNA was performed on Day 7.	Drug: Grazoprevir; GZR 100 mg tablet by mouth q.d. for 7 days.; Other Names: MK-5172

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Estimated Area Under the Liver Concentration-time Curve for 24 Hours Post-dose (AUC[H]0-24hr) of Grazoprevir	Each participant was assigned to undergo Fine Needle Aspiration (FNA) to obtain liver tissue at different time points. Specifically, one participant underwent FNA at 4 hr post-dose only, another participant underwent FNA at 8 hr post-dose only, and a third participant underwent FNA at 24 hr post-dose only. (The fourth participant underwent FNA at 72 hr post-dose and therefore was not included in the calculation of AUC0-24hr.) Therefore, in calculating AUC0-24hr, there were only 3 data points: 1 data point at 4 hr post-dose, 1 data point at 8 hr post-dose, and 1 data point at 24 hr post-dose. The model assumed that drug concentration was at steady-state, and that the concentration at 24 hr post-dose was equal to the concentration at 0 hr post-dose.	4, 8, and 24 hours post-dose on Day 7
Hepatic Concentration of GZR (C[H]Xhr)	C(H)Xhr of GZR was expressed as liver concentration (μmol GZR/L liver) using the concentration of the extracted liver sample (mass of the liver biopsy/0.2 mL solvent), and assuming that liver has the specific gravity of water (1 g/mL). The arithmetic mean C(H)Xhr concentration is based on the means of 4 FNA passes per participant in all 4 participants.	4, 8, 24, and 72 hours post-dose on Day 7
Apparent Terminal Hepatic Half-life (t[H]½ ) of GZR	t(H)1/2 is a measure of the time required for the maximum post-dose liver concentration of GZR to decrease by 50%.	4, 8, 24, and 72 hours post-dose on Day 7

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma AUC[0-24 hr] of GZR	AUC0-24hr is a measure of the mean concentration of drug in plasma after dosing to 24 hours post-dose.	Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 and 72 hours post-dose on Day 7
Maximum Plasma Concentration (Cmax) of GZR	Cmax is a measure of the maximum plasma concentration post-dose.	Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 and 72 hours post-dose on Day 7
Lowest Plasma Concentration (Ctrough) of GZR	Ctrough is a measure of drug concentration 24 hours post-dose.	Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 and 72 hours post-dose on Day 7
Time to Maximum Plasma Concentration (Tmax) of GZR	Tmax is a measure of time to reach maximum post-dose plasma drug concentration.	Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 and 72 hours post-dose on Day 7
Plasma t½ of GZR	t1/2 is a measure of time for the maximum plasma concentration of GZR to decrease by 50%.	Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 and 72 hours post-dose on Day 7

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2013
• Primary Completion (Actual): July 31, 2014
• Study Completion (Actual): July 31, 2014

Study Registration Dates

• First Submitted: February 17, 2012
• First Submitted That Met QC Criteria: February 17, 2012
• First Posted (Estimate): February 23, 2012

Study Record Updates

• Last Update Posted (Actual): September 14, 2018
• Last Update Submitted That Met QC Criteria: August 16, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Hepatitis; Hepatitis A; Hepatitis C; Anti-Infective Agents; Antiviral Agents; Grazoprevir
• Other Study ID Numbers: 5172-010; 2011-000435-83 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf